Background: Smoking is a risk factor for incident colorectal cancer (CRC); however, it is unclear about its influence on survival after CRC diagnosis.

Aim: We aimed to examine the association of smoking with all-cause (overall survival; OS) and disease-free survival (DFS) among CRC patients and to assess potential interactions of smoking with sex, age at diagnosis, and tumor molecular phenotype on cancer mortality.

Methods: A cohort of 706 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and recurrence until April 2010. Smoking and relevant co-variable data were collected by questionnaire after cancer diagnosis. Molecular analyses of MSI status and BRAF mutation status were performed in tumor tissue using standard techniques. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards regression, controlling for major known prognostic factors.

Results: Comparing to never smokers, overall survival was significantly poorer for current (HR: 1.78; 95% CI: 1.04-3.06), but not former (HR: 1.06; 95% CI: 0.71-1.59) smokers, although this association was limited to tumors in the colon. The associations of cigarette smoking with the study outcomes were higher among patients with >40 pack years of smoking (OS: HR: 1.72; 95% CI: 1.03-2.85; DFS: HR: 1.99, 95% CI: 1.25-3.19), those who smoked ≥30 cigarettes per day (DFS: HR: 1.80, 95% CI: 1.22-2.67), and those with MSS/MSI-L tumor (OS: HR: 1.38, 95% CI: 1.04-1.82; DFS: HR: 1.32, 95% CI: 1.01-1.72). Potential heterogeneity was noted for sex (DFS: p for heterogeneity=0.04, HR: 1.68 for men and 1.01 for women) and age at diagnosis (OS: p for heterogeneity=0.03, HR: 1.11 for patients aged <60 and 1.69 for patients aged ≥60), while the stratified results for tumor molecular phenotype were more equivocal.